Metastasis remains the primary cause of patient morbidity and mortality. The reality is that we are not detecting secondary lesions at an early enough stage to make meaningful intervention. There is a burgeoning field investigating the role of tissue mechanics and architecture in normal tissue maintenance and in cancer promotion. However, the field is still struggling to decouple the physical from the better-known biochemical determinants of cell fate. Simply put, how do the physical properties of the tissue environment influence the emergence of tumor promotion or tumor suppression? The bulk of our current understanding is derived from characterization of mechanical properties of tissues, cells, and ECM hydrogels using bulk rheological or nm scale techniques such as Atomic force microscopy (AFM).The Tanner lab developed new 3D culture models, incorporating architectural complexity with well-defined extracellular matrix ligand availability to mimic physiological tissue. In addition, we developed tools that directly quantitate the physical cues that a cell will see in vivo within native tissue, and in the presence of physiologic noise, to finally address these questions. To achieve this in vivo characterization, the Tanner lab designed and built a microscope that employed active microrheology optical trapping in vivo, which allowed for the quantitation of mechanical heterogeneities with micrometer spatial resolution in living zebrafish.